Method for control of helminths in warm-blooded animals using phosphinyldithiocarbamates.

ABSTRACT

This invention relates to a novel method for controlling helminths in warm-blooded animals. More particularly, the invention relates to a method for the control of helminths in warm-blooded animals by administering to said animals, an anthelmintically effective amount of a compound of the formula:   WHEREIN R and R1 are each members selected from the group consisting of loweralkyl, loweralkoxy and phenyl; X is sulfur or oxygen; and R3 is a loweralkylene radical, such as ethylene, loweralkyl substituted ethylene, trimethylene, loweralkyl substituted trimethylene, oxydimethylene, tetramethylene or loweralkyl substituted tetramethylene.

a United States Patent Doscher 51 June 20, 1972 [54] METHOD FOR CQNTROL 0F Primary Eraminer-Sam Rosen HELWNTHS IN WARM-BLOODED Attorney-Stephen Raines ANIMALS USING PHOSPHINYLDITHIOCARBAMATES.

{72] Inventor: Mary Ehlers Doscher, Trenton, NJ.

[73] Assignee: American Cyanamid Company, Stamford,

Conn.

[22] Filed: April [5, I971 [21 Appl. No.: 134,454

{52 1 u s. Cl ..424/205 [5 l Int. Cl. A6lk 27/00 [58] Field of Search ..424/205 [56] References Cited UNITED STATES PATENTS 3,402,224 9/1968 Schicke .Q ..424/205 2,9 I 6,415 12/1959 Willard et al. ..424/205 [57] ABSTRACT This invention relates to a novel method for controlling helminths in warm-blooded animals. More particularly, the invention relates to a method for the control of helminths in warm-blooded animals by administering to said animals, an anthelmintically effective amount of a compound of the forwherein R and R, are each members selected from the group consisting of loweralkyl, loweralkoxy and phenyl; X is sulfur or oxygen; and R is a loweralkylene radical, such as ethylene. loweralkyl substituted ethylene. trimethylene. loweralkyl substituted trimethylene, oxydimethylene, tetramethylene or loweralkyl substituted tetramethylene.

10 Claims, No Drawings DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention are described in US. Pat. application Ser. No. 58,677, filed'luly 27, i970 which is acontinuation-in-part of a US. Pat. application Ser. No. 640,836, filed May 24, 1967 now abandoned.

US. application Ser. No. 57,677, filed July 27, 1970 reports alkylene-bis-phosphinyldithiocarbarnates to be highly effective plant pesticides and are particularly effective against insects and arachnidswhich ravage living plants. A new use, not suggested by the earlier application, as an anthelmintic in warm-blooded animals has now been found for alkylene-bisphosphinyldithiocarbamates.

It has been found that alkylene-bis-phosphinyldithiocarbamates have relatively low mammalian toxicity and are highly effective against a variety of helminths in domestic, fann, fur and laboratory animals.

In general, the compounds which are useful in the method of the present invention, i.e., the treatment of warm-blooded animals to prevent, reduce and/or control helminth infestations in such animals, have the formula:

\ii I i: /'l'--Nl[JJS-.-R I 7 R1 |2 whercin R and R are members sclectedfrom the group consisting of loweralkyl, loweralkoxy and phenyl; X is sulfur or oxygen; R isethylene, loweralkyl andsubstituted ethylene, trimethylene, loweralkyl substituted trimethylene, ox-

ydimethylene, tetramethylene or loweralkyl substituted .tetramethylene.

Such compounds-are prepared by reacting a phosphinyl' isothiocyanate of the formula;

tant are used per mole of the alkylene dithiol. However, the.

molar ratio may be varied somewhatwith'out seriously alten'ng product yield. Advantageously, the-reaction can be carried out over a wide range of temperatures, usually betweenabout and 100 C., but it is preferred to conduct the reaction at a temperature between about 30' and 60 C. Graphically, the over-all reaction may be illustrated as follows:

wherein R, R R X and M are as hereinabove defined.

lllustrative of the alkylene-bis-phosphinyldithiocarbamates so prepared are: ethylene-bis-diethoxyphosphinyldithiocarbamate, methylene-bis-dimethoxyphosphinyldithiocarbamate, propylene-bisdiethylphosphinyldithiocarbamate, tetramethylene-bis-dibutoxyphosphinyldithiocarbamate, 1,2- butylene-bis-ethoxyphenylphosphinyldithiocarbamate,' 2,3- butylene-bis-diethoxyphosphinyldithiocarbamate, 2,2- dimethyltrimethylene-bis-methylphenylphosphinyldithiocar- 2 bamate, ethylene-bis-diphenylphosphinyldithiocarbamate, methylene-bis-diethoxyphosphinothioyldithiocarbamate, propylene-bis-diethoxyphosphinothioyldithiocarbamate,

ethylene-bis-phosphinothioyldithiocarbamate.

An alternative method of preparing the compounds of the present invention is to treat the phosphinyl isothiocyanates of the formula:

with an alkali metal hydrosulfide MSH; yielding the corresponding phosphinyldithiocarbamate salt:

wherein- R, R,, and M arehereinabove defined. Where the latter salt is reacted with bis-chloromethylether'andthe reaction mixture acidified, there are formed oxydimethylene bisphosphinyldithiocarbamates of the formula:

lllustrative of the oxydimethylene-bis-phosphinyldithiocarbamates so prepared are: oxydimethylene-bis-diethoxyphosphinyldithiocarbamate, oxydimethylene-bis-dimethoxyphosphinyldithiocarbamate, oxydimethylenebis-dimethylphosphinyldithiocarbamate, oxydimethylene-bis-methoxyethylphosphinyldithiocarbamate, oxydimethylene-bisdiphenylphosphinyldithiocarbamate.

ln-practice, the activecompounds are generally orally administered to host animals in' a capsule, pill, bolus, tablet, drench-or liquid formulation or added to or admixed with-the feed. However, if desired, the compoundsmay also-beadministered. by injection subcutaneously or'intramuscularly. Amongthe animals whichmay be effectively treated with compounds of the present invention are cattle, sheep, dogs, goats, horses, rabbits, guinea pigs, swine, and foxes.

lnaddition, these compounds may be used in mixtures with other usefulanthelmintic agents when administered to warmbloodedanimals. Such combinations may result in obtaining a wider range of activity and add to convenience of administration. An example done such useful combination is the combining'ofan alkylene-bis-phosphinyldithiocarbamate and maminotetramisole (imidazo[2, 1 -b]thiazole, 6-( m-arninophenyl)-2,3,5;6-tetrahydro-l-dihydrochloride). The methods of administration of the mixtures are the same as those listed for administering the alkylene-bis-phosphinyldithiocarbamate as a single active component.

Usually from about 2.5 to 30 mg. of the alkylene-bis-phosphinyldithiocarbamate per kg. of animal body weight and preferably 5.0 to 15 mg./kg. is effective for controlling'helminthiasis in such animals. Treatment may conveniently be given as a single dose within the stated range or the dose may be reduced to from A to 1/20 of the above mentioned level and administered in multiple doses.

Although the compounds of the above-identified structure are useful in the treatment of a wide variety of animals, it isinteresting to note that such compounds are particularly effective in Canidae treatment.

Compounds which are especially useful in the latter'treatmentsare those of the formula:

wherein R and R are ethoxy and R is as described above; ethylene-bis-diethoxyphosphinyldithiocarbamate, trimethylene-bishdiethoxyphosphinyldithiocarbamate, propylene-bis-diethoxyphosphinyldithiocarbamate and oxydimethylene-bisfdiethoxyphosphinyldithiocarbamate being among the most active of these materials. a

The invention will be further illustrated in conjunction with the following examples.

Example 1 Preparation of Ethylene-bis-Diethoxyphosphinyldithiocarbamate The sodium salt of ethanedithiol is obtained as a colorless solid by adding the dithiol to excess sodium methoxide in ethanol under nitrogen followed by addition thereto of benzene. It is washed with ethanol-benzene and then with ether and dried in vacuo. To a cooled (room temperature) mixture of 8.5 parts of diethoxyphosphinyl isothiocyanate in 100 parts (by volume) of benzene is added 3.0 parts of ethanedithiol sodium salt. After an hour, 10 parts (by volume) of the stirred mixture is removed and the very fine solids are spun down in the centrifuge and washed with one part of ether. The nuclear magnetic resonance spectrum in deuterium oxide shows a singlet at 6.80)1(-CH,S, 4H), a multiplet at 5.9)\(CH --O, 8H), and a doublet at 8.68)\(CH C, 12H).

The remainder of the reaction mixture is mixed with water and the phases are separated. Thebenzene phase is washed several times with water. The combined water fractions arefiltered, washed oncewith ether, poured into a flask, ice-cooled and acidified with 25 percent hydrochloric acid. The precipitated solids are washed several times with water and vacuum dried at 45 to 50 C. over potassium hydroxide leaving 8.7 parts (84 percent based on work-up of 90 percent of the intermediate salt) of pale yellow crystals, melting point 115 to 118 C. Recrystallization by dissolving 5.0 parts in ethanol with slight warming followed by dilution with two volumes of hexane and cooling to 20 C. gives 3.4 parts of veryfine pale yellow crystals, melting point 120 to 125 C. at 1/minute (dec.).

Analysis Calculated for C H N O P S i C, 29.74; H, 5.29; N,-5,78; P, 12.79; S, 26.47.

Found: C, 30.14; H,'5.l3; N, 5.75; P, 12.65; S, 26.66.

The infrared spectrum shows strong maxima at 1240, 1280, 1480, and 3080 cm, the latter two assignable to the NH group. The nuclear magnetic resonance spectrum in deuterochloroform shows a doublet at 0.l)\(v=8 ppm, N--H, 2H), a singlet at 6.40).(SCH, 4H), a multiplet at 5.7v(CH,O-, 8H), and a triplet at 8.58)\(v= 7 ppm., CH;,-C, 12H).

Utilizing the same procedure employed above to prepare ethylene-bis-diethoxyphosphinyldithiocarbamate but with the indicated substitution of reactants, the following analogs are prepared.

A. Preparation of Trimethylene-bis-Diethoxyphosphinyldithiocarbamate By substituting propane-1,3-dithiol for ethanedithiol, melting point 89 to 90C.

Analysis Calculated for C13H2flNzO P2S4: C, 31.31; H, 5.66;

N, 5.62; P, 12.42; S, 25.72.

Found C, 31.29; H, 5.84; N, 5.79; P, 12.24; S, 25.48.

B. Preparation of Propylene-bis-Diethoxyphosphinyldithiocarbamate By substituting propane-.l,2-dithiol for ethanedithiol, melting point 1 14t0 115 C.

Analysis Calculated for C, H, N O P S C, 31.31; H, 5.66;

N, 5.62; P, 12.42; S, 25.72.

Found: C, 31.42; H, 5.80; N, 5.72; P, 12.64; S, 25.91.

C. Preparation of Ethylene-bis-Diethoxyphosphinothioyldithiocarbamate.

By substituting potassium diethoxyphosphinothioyldithiocarbamate, melting point 105 to l 10C.

Analysis Calculated for C, H NO,P,S C, 27.89; H, 5.07;

N, 5.42; P, 11.99; S, 37.24.

Found: C, 28.00; H, 5.27; N, 5.60; P, l 1.78; S, 37.20.

D. Preparation of Trimethylene-bis-Diethylphosphinyldithiocarbamate I By substituting diethylphosphinyl isothiocyanate for diethoxyphosphinyl isothiocyanate, and trimethylenedithiol sodium salt for ethanedithiol sodium salt, trimethylene-bisdiethylphosphinyldithiocarbamate was obtained in good yield. E. Preparation of 2,3-Butylene-bis-Ethoxypheny1phosphinot ioyldithiocarbarbamate.

Substituting ethoxyphenylphosphinothioyl isothiocyanate for diethoxyphosphinyl isothiocyanate, and 2,3-butanedithiol sodium salt for ethanedithiol sodium salt resulted in the formation of 2,3-butylene-bis-ethoxyphenylphosphino hioyldithiocarbamate in good yield. 7 F. Preparation of Tetramethylene-bis-Diphenylphosphinyl dithiocarbamate By substituting diphenylphosphinyl isothiocyanate for diethoxyphosphinyl isothiocyanate, and tetramethylenedithiol sodium salt for ethanedithiol sodium salt tetramethylene-bisdiphenylphosphinyldithiocarbamate was obtained in good yield.

EXAMPLE 2 Preparation of vOxydimethylene-bisDiethoxyphosphinyldithiocarbamate To an ice-cooled mixture of 0.9 part of bis-chloromethyl ether in 10 parts (by volume) of dry acetone is added 2.0 parts of potassium diethoxyphosphinyldithiocarbamate. After 30 minutes, the bath is removed and the mixture is stirred overnight. Filtration followed by concentration in vacuo gives 1.6 parts of yellow solids. The solids'crystalli ze at room temperature from about 3:1 chloroform as pale yellow crystals, melting point 986 to 99.6 C., 1.1 parts (58 percent).

Analysis Calculated for C, H N O,P S C, 28.79; H, 5.24;

N, 5.60; P, 12.38; S, 25.62.

. Found: C, 28.61; H, 5.30; N, 5.75;'P, 12.12; S, 25.63.

The infrared spectrum shows bands at 1,480 cm and 3,050 cm? attributable to the group and at 1,240 cm for the P 0 function.

Substituting potassium ethoxyphenylphosphinyldithiocar bamate for the potassium diethoxyphosphoryldithiocarbamate results in the formation of the compound oxydimethylene-bisethoxyphenylphosphinyldithiocarbamate.

EXAMPLE 3 Testing was done in young mongrel dogs with natural or experimental infections of one or more of the following helminths: Hookworms-Ancylostomum cam'num, Uncinan'a stenocephala; RoundwormsT0xocara canis, Toxascan's leonina; TapewonnsDipylidium caninum, Taenia pisrformis. Dogs were determined to be infected by finding eggs in the feces in the case of the nematodes, and proglottids in the case of tapeworms.

Compounds were administered orally in gelatin capsule. Dogs were not starved prior to treatment.

After dogs were treated all feces were collected and washed through mesh screens. Material retained in the screen was examined for worms which were identified and counted. Dogs were necropsied after their feces had been negative for worms for 2 days. At necropsy the worms remaining in the intestines were counted and numbered remaining compared with those passed to find percent efi'icacy of the compound. Dogs with tapeworm infections were held for at least 2 weeks following treatment'before necropsy. I

D. caninum scolices were either dissolved or so badly damaged by these compounds that they were not recovered average worm burden per dog.

phenyl; X is a member selected from the group consisting of sulfur and oxygen and R is a member selected from the group consisting of loweralkylene radical C,-C and oxydimethylene.

2. A method according to claim I wherein X is oxygen.

3. A method according to claim 2 wherein the'host animal is of the family Canidae.

4. A method according to claim 1 wherein said compound is administered to said host animal orally at from 2.5 to n g/lrg. of body weight.

1. A method for the control of helrninths in wann-blooded animals comprising; administering to host animals in which helrninth control is desired an anthelmintically effective amount of a compound having the formula:

- wherein R and R each represent a member selected from the group consisting of loweralkyl C -C loweralkoxy C,-C and TABLE I A. canz'num T. canis T. leom'n z Single oral Num Number of 'OI'IIIS Number of wonns N umber of worms dose, ber of Percent Percent Percent Compound mgJkg. dogs Passed Retained elfieacy Passed Retained ellieaey Passed Retained ellicacy Carbamic acid (diethoxyphosphin- I yl)dithioethylene ester 5 1 16 4 15 0 100 Carbamie acid (diethoxyphosphinyDdithiotr-imethylene ester 5 2 164 9 G2 5 U5 Carbamic acid (diethosyphosphinyl)dithiopropylene ester 5 2 146 9 89 l 0 8 1 80 C arbamie acid (diethoxyphosphinylJdithiooxydimethy-lene ester. 5 1 0 0 15 a No necropsy.

I claim: 25 5. A method according to claim 1 wherein said compound is administered to said host animal orally at from 5.0 to 15 mgJkg. of body weight in a single dose.

6. A method according to claim 1 wherein said compound is administered to said host animal in multiple doses.

7. A method according to claim 1 wherein the compound is ethylene-bis-diethoxyphosphinyldithiocarbamate.

8. A method according to claim 1 wherein the compound is ox dimeth lene-bis-diethoxyphosphin ldithiocarbamate.

. A me od according to claim 1 w erein the compound is trimethylene-bis-diethoxyphosphinyldithiocarbamate.

10. A method according to claim 1 wherein the compound is propylene-bis-diethoxyphosphinyldithiocarbamate.

* i t i 

2. A method according to claim 1 wherein X is oxygen.
 3. A method according to claim 2 wherein the host animal is of the family Canidae.
 4. A method according to claim 1 wherein said compound is administered to said host animal orally at from 2.5 to 30 mg./kg. of body weight.
 5. A method according to claim 1 wherein said compound is administered to said host animal orally at from 5.0 to 15 mg./kg. of body weight in a single dose.
 6. A method according to claim 1 wherein said compound is administered to said host animal in multiple doses.
 7. A method according to claim 1 wherein the compound is ethylene-bis-diethoxyphosphinyldithiocarbamate.
 8. A method according to claim 1 wherein the compound is oxydimethylene-bis-diethoxyphosphinyldithiocarbamate.
 9. A method according to claim 1 wherein the compound is trimethylene-bis-diethoxyphosphinyldithiocarbamate.
 10. A method according to claim 1 wherein the compound is propylene-bis-diethoxyphosphinyldithiocarbamate. 